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International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 11, Issue 1, 2019

Review Article A REVIEW ON CO-PROCESSED EXCIPIENTS: CURRENT AND FUTURE TREND OF EXCIPIENT TECHNOLOGY

LIEW KAI BINab*, ANAND GAURAVa, UTTAM KUMAR MANDALc aFaculty of Pharmaceutical Sciences, UCSI University. No 1, Jalan Menara Gading, UCSI Height, 56000 Cheras, Kuala Lumpur, bFaculty of Pharmacy, Cyberjaya University College of Medical Sciences. Persiaran Bestari, 63000 Cyberjaya, Selangor, cDepartment of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University (MRSPTU), Bathinda, Punjab 151001, India Email: [email protected] Received: 21 Aug 2018 Revised and Accepted: 23 Nov 2018 ABSTRACT There is no single-component excipient fulfills all the requisite performance to allow an active pharmaceutical ingredient to be formulated into a specific . Co-processed excipient has received much more attention in the formulation development of various dosage forms, specially for preparation by direct compression method. The objective of this review is to discuss the emergence of co-processed excipients as a current and future trend of excipient technology in pharmaceutical manufacturing. Co-processing is a novel concept of combining two or more excipients that possess specific advantages that cannot be achieved using a physical admixture of the same combination of excipients. This review article discusses the advantages of co-processing, the need of co-processed excipient, general steps in developing co-processed excipient, limitation of co-processed excipient, technologies used in developing co-processing excipients, co-processed excipients in the literature, marketed products and future trends. With advantages offered by the upcoming newer combination of excipients and newer methods of co-processing, co-processed excipients are for sure going to gain attraction both from academia and pharmaceutical industry. Furthermore, it opens the opportunity for development and use of single multifunctional excipient rather than multiple excipients in the formulation. Keywords: Orally disintegrating tablet, Oral delivery, Co-processed excipient, Direct compression © 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open-access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijpps.2019v11i1.29265

INTRODUCTION processing. However, in the case of co-processed excipients, they possess performance advantages that cannot be achieved using a In the past 10 y, the focus of both academia and pharmaceutical physical admixture of the same combination of excipients [11]. industry has been shifted from developing new active Combination of economical excipient with others of optimal quantity pharmaceutical ingredient (API) to formulation technology [1]. of a functional material will produce an integrated product with Pharmaceutical excipients have played a major role in that shift. superior functionality than the simple mixture of components [12]. Pharmaceutical excipients are defined as the substances other than Co-processing generally does not involve chemical change. The the API which has been appropriately evaluated for safety and are changes in functionality are often contributed by the change in intentionally included in a system [2]. The physical properties of the excipient particles [13]. International Pharmaceutical Excipients Council (2009) defines excipients as the substances which present in a finished Oral delivery remains the most popular route of drug delivery [14]. pharmaceutical dosage form other than the active drug substance It is because the oral drug delivery system has the key advantage of [3]. Excipient can be classified into four categories generally: single convenient drug administration. Tablets and hard capsules entity excipient, a physical blend of multiple excipients, new constitute a major portion of drug delivery systems that are chemical entity excipient and co-processed excipient [4]. currently available due to its convenience of self-administration, compactness and simple manufacturing process [15, 16]. Moreover, It is generally agreed by the formulation scientist that there is no the drug is found to be more stable in solid dosage form than liquid single-component excipient fulfills all the requisite performance to dosage form [17]. allow an active pharmaceutical ingredient to be formulated into a specific dosage form [5]. On the other hand, developing a new The most common methods to manufacture tablets are wet chemical entity excipient requires a huge sum of investment [6]. To granulation, dry granulation and direct compression [18]. If the counter this issue, formulation scientist has introduced a novel major components of a formulation have already possessed good concept of co-processing which is combining of two or more fluidity and compressibility, granulation would be redundant. Direct excipients that possess significant advantages that cannot be compression was reported as one of the most preferred methods achieved using a physical admixture of the same combination of due to some advantages such as time-saving, ease of production due excipients [7]. A co-processed excipient is a combination of two or to few steps involved, the absence of heat and moisture in the more compendial or non-compendial excipients designed to modify process [19]. In the survey by Shangraw and Damarest (1993), it their physical properties in a manner not achievable by simple was shown that direct compression was the most preferred tablet physical mixing, and without significant chemical change [2]. By manufacturing method compared to wet granulation and roller formulating few excipients into a single composite material with compaction. About 41% of the companies indicated that direct specialized manufacturing method leads to an improvement in compression was the method of choice, and 41.1% indicated that functionality of the end product [8]. This has become a newer trend they used both direct compression and wet granulation. Only 1.7% in formulation development [9]. of the respondents indicated that they never used direct compression and 15.5% indicated that the process was not Co-processed excipient has received much more attention in the recommended [19]. formulation development of various dosage forms such as a tablet, , , cream, ointment, and others [10]. It is different A further advantage of direct compression is that tablets disintegrate from the physical mixture. Physical mixture is just a simple into the primary particles bypassing granular aggregation stage. As a admixture combining few excipients by short duration shear result, the effective surface area increases and dissolution of the drug

Liew et al. Int J Pharm Pharm Sci, Vol 11, Issue 1, 1-9 become faster [20]. However, the method encounters drawbacks due processed adjuvants, by virtue of their high solubility, swelling and to lack of suitable excipients for direct compression application. Two wicking property, provide rapid disintegration to the developed major factors of powder characteristic which will critically affect the formulation. process of direct compression are compressibility and flowability [21, 22]. The majority of the excipients that are currently available fail to Stability meet the desired set of functionalities. It creates urgency for the The co-processed excipient should be stable physically and chemically development of high functionality excipients [23]. Therefore, the co- [6]. The ingredients used should be inert and not interact with the API. processed excipient can play a role here to fill the gap of technology in direct compression. Cost saving The aim of this article was to perform a literature review on co- The manufacturer uses a single excipient with multiple functional processed excipient and compile as well as discussing the co- properties, thereby reducing the number of excipients used and processed excipients available in the market and in literature. A labor cost involved in their processing other than direct detail literature review was conducted by searching keywords such compression method. Use of co-processed adjuvants simplifies as: a co-processed excipient, orally disintegrating tablet, oral drug manufacturing process which leads to time and cost saving. delivery, tablet, direct compression, formulation, solid dosage form and powder. The search was done in the search engines including Need of co-processed excipients Science Direct, Science and Technology of Advanced Materials, PLOS A list of available co-processed excipients is provided in table 1. However, ONE, Directory of Open Access Journals, CiteSeer and Google Scholar. they are not sufficient considering the diverse need of the pharmaceutical industries, specially for preparation of ODT tablets. Advantages of co-processing There are only a few excipients are suitable for direct compression Improved compressibility application. Most of the excipients having drawbacks such as lack of compressibility, poor flowability, lack of cohesion properties or Compressibility is an important factor of consideration in tablet lubrication [32]. As a result, a blend of few ingredients is required to development. Ideally, a compacted tablet is formed once the achieve satisfactory condition prior to direct compression [33]. compression force is removed (6). However, all the conventional tablet Moreover, the advance in tableting machinery has resulted in high-speed excipients lack this plastic property. Majority of the co-processed tablet machine with short duel times. Operation of this machine requires adjuvants overcome this limitation. Flores et al. (2000) reported that the excipients with good compressibility flow property [4]. compressibility of Ludipress®, a co-processed adjuvant, is superior than the physical mixtures of their constituent excipients [24, 25]. The role of co-processing comes into the picture by interacting two or more excipients at the sub-particle level, aimed at providing a Better dilution potential synergy of functionality improvements, as well as masking the Dilution potential is defined as the ability of the excipient to retain its undesirable properties of the individual excipients [2]. The compressibility even when diluted with another low compressibility advancement and maturation of co-processing technology explore material. API and many inactive excipients have poor compressibility. On the possibility to produce tailor-made “designer excipients” to cater the other hand, a co-processed excipient with high dilution potential is to various specific needs required for formulation development [32]. desirous so that the compressibility properties of the mixture of powder General steps in developing co-processed excipients blend can be maintained even when diluted with other excipients [26]. Cellactose® is shown to have a higher dilution potential than the In order to design a new co-processed excipient which meets the physical mixture of its constituent excipients [27]. functionality requirement of a specific application, few steps are important to take into consideration. Reduced lubricant sensitivity a. Identification of the group of excipients to be co-processed Generally, hydrophobic lubricant provides a negative impact on the compression behavior of powder blend. Plasticity contributes brittle A good co-processed excipient should look into the balance between characteristic to an excipient. The presence of a large degree of plasticity and brittleness of a material [34]. Combination of plastic brittle character in a co-processed excipient provides low lubricant and brittle material nullifies storage of undesirable elastic energy sensitivity because it prevents the formation of a coherent lubricant during the compression. This will produce a product with a small network by forming newly exposed surfaces upon compression, thus amount of stress relaxation and a reduced tendency of capping and breaking up the lubricant network [6]. lamination thereby optimum tableting performance [35]. The combination of excipient chosen should complement each other and Ease of production provide synergistic effect to achieve the desirable characteristics [6].

Co-processed excipient simplifies the tablet formulation and b. Assessing the particle size development steps. Tablet formulation normally consists of weighing of active ingredient and various excipients followed by Particle size will affect the compressibility and flowability of the end mixing, granulation, drying, sieving, and compression. Weighing of product. If the participating excipients have variation in initial each ingredient might be time-consuming, and it may incur error in particle sizes, the focus should be given to produce the final co- the process. Use of co-processed excipient might simplify the processed adjuvant with uniform particle size. production process and reduces the rate of error [28]. c. Selecting a suitable technique to co-process various excipient Improved flow properties There are many methods which can be used for co-processing such The co-processed excipient is reported to have better flow as wet granulation, melt granulation, freeze drying, spray drying, hot properties compared to its individual constituent or physical melt extrusion [36-39]. A comprehensive detail has been provided mixture by controlling the particle size distribution [29]. Good later in this review. flowability is desired especially in case of high-speed rotary tablet d. Optimizing the process and the proportion of each excipient machine [6]. The co-processing excipients play an important role in improving flow property of the powder mass ready for compression. This can contribute to functionality variations in the end product. A study showed that the co-processed Cellactose® has better flow Various optimization techniques and experimental designs with than and due to the spray drying technique used sound statistical analysis can be employed to obtain a final product which resulted in particles of spherical shape and even surfaces [30]. with desired functionalities. Fast disintegration Limitation of co-processed excipient Fast disintegration is compendial and formulation requirement for Although co-processed excipient shows a list of promising benefits, immediate release and orally disintegrating dosage form [31]. Co- however, there are few drawbacks in using of co-processed

2 Liew et al. Int J Pharm Pharm Sci, Vol 11, Issue 1, 1-9 adjuvants. Co-processed adjuvant is available as pre-mixed at a fixed premixed and passed through a high-speed milling machine. During ratio of an individual constituent. The user has no freedom to the process of milling, the particles come in contact with each other alternate the ratio of the excipient [40]. Moreover, co-processed and form bonds when they are subjected to force to mill or pass adjuvant lacks the official acceptance in pharmacopeia [41]. For this through the screen. Rao et al. (2012) applied this technique to co- reason, a co-processed adjuvant is not accepted by the process cross-linked and calcium silicate [55]. pharmaceutical industry unless it exhibits significant advantages in the tablet compaction when compared to the physical mixtures of Melt granulation the excipients [2]. The blend of excipients are mixed with a meltable binder (normally Technologies used in the manufacturing of co-processed at solid state below 80 excipients roller compaction melting point of the binder with continuous blending in order to break the mass into ˚C).agglomerates. The mixture The is subjected cooled agglomerates to heat above arethe Roller compaction uses the principle of dry granulation for particle finally screened to obtain granules with desired size [56-57]. bonding. This method is useful for ingredients which are sensitive to moisture and heat. The powder blend is mixed uniformly and Solvent evaporation compressed between counter-rotating rollers to form a ribbon of Solvent evaporation takes place in a liquid manufacturing vehicle. compacted material that is then milled into granules of appropriate The coating excipient is dissolved in a volatile solvent which is particle size [42-44]. immiscible with the liquid manufacturing vehicle, followed by dissolving or dispersing the core excipient in the coating solution. Wet granulation Agitation force is applied to achieve the desired encapsulation size. Wet granulation is a conventional and simple method for co- Heat is used to evaporate the solvent [4]. processed adjuvant production. Fluid bed granulators and high- shear mixers are two commonly used equipment used for the same. Co-processed excipient in the literature In fluid bed granulation, the powder mix is subjected to fluidization Microcrystalline cellulose (MCC) and by a flow of air injected upwards through the bottom screen of the granulator. The binding solution is sprayed in the opposite direction Mehra et al. (1986) patented a co-processed excipient of to the air flow on the powder bed. The solid particles are mixed with microcrystalline cellulose and calcium carbonate. The co-processed the liquid droplets and hit the bed which results in adhesion and excipient was used to produce a directly compressed vitamin tablet. eventually the formation of granules. Partial drying by the fluidizing The invention was economical and exhibited low lubricant air occurs continuously during granulation [45-47]. sensitivity [58]. In high-shear granulation, an impeller maintains the powder in Lactose, polyvinylpyrrolidone (PVP) and crospovidone agitation in a closed vessel. The binder solution is sprayed from the Lang (1991) reported a blend of lactose, PVP and crospovidone top. Development of large agglomerates is prevented by high shear which was produced through spray drying, spray granulation or wet force. With the new single-pot technology, drying occurs in the same granulation method. The novel direct tableting auxiliaries exhibited system. The granules formed are understandably denser than those good flow, good compressibility under low pressure, excellent obtained in fluid bed granulation [48]. disintegration properties coupled with great hardness and low Hot melt extrusion abrasion [59]. Hot melt extrusion uses heat with a temperature greater than 80 °C. β-lactose and This method is not suitable for thermo labile materials. The Meggelaars (1996) prepared a homogeneous mass consisting excipients are melted and then pressurized through the die and et al. -lactose content with sorbitol ranges solidify into a variety of shapes. The solvent is not required in the from 1-15% % w/w. Roller drying technique was used in the drying process as the molten can function as a thermal binder [49]. prof oacess. dried The solution excipient of canhigh be β used to prepare tablet with exclusive Spray drying hardness [52]. Spray drying generally involves five steps: Concentration of Cornstarch and polyvinylpyrrolidone feedstock, atomization, droplet-air contact, droplet drying and Menon (1996) described a co-processed excipient consisting of separation and collection [50-51]. The technique transforms a feed et al. cornstarch and polyvinylpyrrolidone produced using fluid bed spray which might be a solution, suspension or dispersion into dried granulation method. The invention is free-flowing and exhibits good particulate form by spraying it into a hot drying medium. The compressibility [60]. particle-particle bonding of excipients occurs during the process. The increased droplet surface area and high temperature cause the Colloidal and MCC formation of spherical shape particles with improved flowability and suitable direct compression application such as Starlac®. Sherwood et al. (1996) patented a novel MCC-colloidal silicon dioxide excipient that was found to be free flowing, possess excellent Roller drying disintegration properties and have improved compressibility A roller dryer is used to dry the homogeneous solution or dispersion relative to normal “off the shelf” commercially available MCC [61]. containing the pre-blended excipients. Meggelaars et al. (1996) Guar gum and MCC applied this technique to co-process lactose with sorbitol and [52]. The temperature used was sufficiently high to obtain an end Ratnaraj and Reilly (1997) produced a co-processed excipient for product that consists principal -lactose in crystalline form. the chewable tablet by thoroughly mixing an aqueous dispersion of MCC and guar gum under high shear conditions at room Co-transformation ly of β temperature. The homogenous dispersion was then spray dried to Co-transformation technique involves the application of heat or an aggregate powder having substantially spheroidal-shaped solvent effect to “open-up” (swelling) the particle of one excipient. particles. The excipient has improved compressibility and mouth The other excipients are incorporated into the “opened-up” feel. It reduces tooth packing [62]. structure of the aforementioned excipient. The augmented excipient strengthens the functionality of the end product [53, 54]. Directly compressible The invention contains 95% sucrose and 5% of maltodextrin. This Milling -based excipient is free-flowing, compressible and has a A roller mill, ball bill, bead mill, millstone mill, jet mill or a hammer mill pleasant taste and mouthfeel which can be helpful in masking the can be used to perform milling or dry grinding. The excipients are bitter taste of API [63].

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MCC and methylcellulose MCC and Augello and Vladyka (1999) invented a co-processed excipient by Slurry of MCC and mannitol were sprayed dried to spherical wet granulating MCC and methylcellulose. The compositions were particulate. The composition had an improved compatibility profile, then subjected to spheronizing into spheres having a smooth lubricant sensitivity, and ejection profile compared to the physical uniform surface. The end product serves as a coating polymer mixture and individual component [71]. which provides complete taste masking of a bitter drug such as ibuprofen while having no adverse impact on the bioavailability of Mannitol and calcium silicate the drug [64]. A co-processed excipient which is suitable for orally disintegrating tablet application was developed by Gandhi (2009). Mannitol MCC and sodium alginate et al. was dispersed in followed by dispersing calcium silicate in the The invention is a wet granulation binder type excipient by Augello solution. The mixture was spray dried to granules. The tablet and Reier (1999). A uniform aqueous slurry of MCC and sodium produced by compression of the excipient disintegrated in less than alginate was formed firstly, followed by drying the slurry to granular 60 seconds [72]. particular [65]. Crospovidone and croscarmellose sodium Alfalfa, MCC and calcium carbonate Nagendrakumar et al. (2009) blended croscarmellose sodium and Ibrahim and Saraiya (2001) developed a co-processed excipient crospovidone in . The mixture was stirred until most of the comprised of alfalfa root, MCC and calcium carbonate. Spray dried ethanol evaporated. The wet coherent mass was sieved and dried in procedure was used in the development process. The said product a hot air oven. The invention serves as a co-processed was applied to formulate vitamin and nutritional supplements [66]. superdisintegrant. It was applied to formulate granisetron fast dissolving tablet [73]. MCC and maltodextrin Mannitol and cellulose Buliga et al. (2002) blended MCC and maltodextrin and sprayed dried the dispersion. The invention was reported to mix with Patel SS and Patel NM (2007) prepared a co-processed excipient of to produce a dry blend that can be used in mannitol and cellulose for dispersible tablet application. The end food and cosmetic application as stabilizer [67]. product was prepared using the freeze-thawing method and was claimed to have an improvement in flowability, compatibility and Rice and MCC dissolution rate of a model drug [9]. Limwong et al. (2004) invented a co-processed excipient comprising Povidone and glyceryl behenate of rice starch and MCC. Composite particles of rice starch and MCC were fabricated by spray-drying technique to be used as a directly Ayyappan et al. (2010) developed a co-processed adjuvant compressible excipient. The compressibility was greater than comprising povidone and glyceryl behenate which was claimed to commercial spray-dried rice starch (Eratab), coprocessed lactose function as binder and lubricant with good flow and compressibility. and microcrystalline cellulose (Cellactose), and agglomerated The co-processed excipient was applied to manufacture tramadol lactose (Tablettose), but, lower than microcrystalline cellulose HCl control release tablet and it provided a drug release profile (Vivapur 101) [36]. comparable with Zydol SR [74]. Calcium phosphate and fatty acid wax Microcrystalline and spray dried lactose Cucula et al. (2006) produced a co-processed excipient containing Dey et al. (2010) produced co-processed excipient of various ratio calcium phosphate and fatty acid wax (glyceryl behenate or glyceryl combination of microcrystalline cellulose, spray dried lactose and palmitostearate) using melt granulation method. Co-processing of pearlitol. The study concluded that co-processed excipient of calcium phosphate with fatty acid wax overcomes the abrasiveness microcrystalline and spray dried lactose at 90:10 % w/w was the and capping issues normally associated with calcium phosphate. It optimum formulation which showed good compressibility and fast was applied to formulate venlafaxine HCL modified release tablet, disintegration. The product was applied to formulate paracetamol and venlafaxine besylate extended-release tablet [68]. orally disintegrating tablet [75]. Sorbitol and mannitol Sodium carbonate and Norman et al. (2006) reported a blend of sorbitol and mannitol The invention is a pH modifier developed by Davar et al. (2010) prepared by dissolving mannitol powder and sorbitol powder into a using a fluid bed spray granulation method. Polyethylene glycol solution. The solution was then dried in an air stream and forming a protects sodium carbonate from moisture which results in caking. composition that completely dissolves in the oral cavity within 60 The said invention was applied in the non-effervescent seconds. The invention is suitable for orally disintegrating tablet pharmaceutical composition of zolpidem and scopolamine [76]. application [69]. Starch and magnesium silicate Crospovidone and sodium starch glycolate Adnan et al. (2011) co-processed starch with magnesium silicate. Gohel et al. (2007) developed the co-processed excipient through Starch was suspended in a suspension first followed by addition of wet granulation and tray drying technique. Blend of crospovidone magnesium silicate. The suspension was then filtered, washed and and sodium starch glycolate was added to isopropyl alcohol for wet dried. The dried product was used to prepare tablets with high granulation. The wet mass was sieved and dried in a tray dryer. The mechanical strength, short disintegration time and low lubricant end product exhibited good flow property, compaction and sensitivity [77]. disintegration property. The invention was applied as a Lactose, MCC and cornstarch superdisintegrant in the formulation of cefiximetri hydrate and ibuprofen tablet [37]. Akram et al. (2011) developed co-processed micro-granules of lactose monohydrate, MCC and cornstarch by wet granulation. The Copolymer of vinylpyrrolidone (VP) and vinyl acetate (VA) and finished product was claimed to have the strong binding ability, fast MCC disintegration time and improved flow property [78]. Halder et al. (2007) developed a co-processed adjuvant containing a α-chitin and mannitol copolymer of vinylpyrrolidone, vinyl acetate and MCC. This synergistic binder composition was applied to produce tablets with Al Omari et al. (2011) published research on the development - exclusive hardness and acceptable friability. It is suitable to be used chitin and mannitol co-processed excipient by fluid bed spray in tablet formulation containing poorly compressible drug [70]. granulation method. The invention was applied in the orallyof α

4 Liew et al. Int J Pharm Pharm Sci, Vol 11, Issue 1, 1-9 disintegrating tablet to contribute to exclusive hardness, low powder samples were forced between two counter-rotating rolls and friability, low ejection force while retaining rapid disintegration screened through 60 mesh sieve. The obtained fine powder was further properties [79]. recycled to get granules of uniform size. The finished product was applied to produce metformin HCl sustained release tablet [83]. Dibasic calcium phosphate, HPMC and crospovidone Dicalcium phosphate and carboxymethylcellulose sodium Deorkar et al. (2011) formulated an invention by co-processing dibasic calcium phosphate as a brittle material component, HPMC as Ambore et al. (2014) studied on various ratio combination of binder and crospovidone as a disintegrant. The invention showed an dicalcium phosphate and carboxymethylcellulose co-processed increased flowability, API loading, and blendability and higher using co-precipitation method. The study concluded that the flow compatibility [80]. property of the co-processed excipient improves significantly compared to the physical mixture. The excipient had good dilution MCC and HPMC potential and was used to produce a tablet with poorly compressible Deorkar et al. (2011) prepared a co-processed excipient by spray such as paracetamol and ibuprofen [29]. dry granulating an aqueous slurry comprised of the microcrystalline Dicalcium phosphate and carboxymethylcellulose sodium cellulose and HPMC. Then invention has enhanced flowability, high compatibility, and increased API loading and blendability as The invention was developed by Ambore et al. (2014) using co- compared to the individual components [80]. precipitation technique. Carboxymethylcellulose was dispersed in water to allow it to swell. Dicalcium phosphate was dispersed in Maize starch and acacia another portion of water. The two portions of dispersion were Olowosulu et al. (2011) developed co-processed excipient of maize mixed and dried in tray dried. The invention was reported to have and acacia by co-drying or a well dispersed aqueous mixture of the better flowability and dilution potential [29]. two. The drying was performed on a water bath system at 50 Chitosan and Eudragit S-100 80 5 min with constant stirring respectively to compare the effect of partial and fully gelatinization. The fully gelatinized˚C form and Pawar et al. (2014) prepared a co-processed excipient of chitosan showed˚C for good1 flowability but poor crushing strength. In contrast, the and Eudragit S-100 using the solvent evaporation method. The co- tablets produced by partially gelatinized form showed good crushing processed excipient was applied to produce venlafaxine HCl strength and friability profile [81]. sustained release tablet via direct compression [84]. Calcium phosphate and MCC Lentinus tuber regium base co-processed excipient Thoorens et al. (2011) invented a calcium phosphate and MCC co- Ugoeze and Nkoro (2015) developed a co-processed excipient by processed excipient by mixing the aqueous slurries of mixing Lentinus tuber regium, sodium bicarbonate, tartaric acid and microcrystalline cellulose and calcium phosphate, followed by using solvent evaporation method. The end product drying such slurries to produce particulate products. The end appears as a compactable, tasteless, off-white powder without product exhibited improved compatibility, as compared to dry distinct odor. The flow property, compressibility, and dilution physical blends of the same components [82]. potential were improved [12]. Polyox WSR-301 and HPMC K4M Marketed products The co-processed excipient was reported by Gangurde and Amin (2013) There are many marketed products of co-processed excipients using roller compaction method. Polyox WSR-301 and HPMC K4M available. The marketed products are presented in table 1.

Table 1: Products of co-processed excipients which are available in the market Trade name Excipients Manufacturer Added advantage Reference Ludipress Lactose, kallidon 30, kallidon CL BASF Low degree of 85 hydroscopicity, good flowability, tablet hardness independent of machine speed Cellactose Lactose and cellulose Meggle High compressibility, good 86 mouth feel, better tableting at low cost Dipac Sucrose and dextrin Penwest Pharm Directly compressible grade 87 Prosolv Microcrystalline cellulose and silicon Penwest Pharmaceuticals Better flow, reduced 88 dioxide sensitivity to wet granulation, better hardness of tablet, reduced friability Avicel ce-15 Microcrystalline cellulose and guar FMC Corp. Less grittiness and minimal 89 gum chalkiness Formaxx Calcium carbonate and sorbitol Merck High compressibility, 90 excellent taste masking, free flow, superior content uniformity, controlled particle size distribution Microcelac Microcrystalline cellulose and lactose Meggle Capable of formulating high 91 dose, small tablets with poorly flowable active ingredients Starlac Lactose and maize starch Meggle Good flowability due to 56 spray drying, the acceptable crushing force due to lactose content and rapid disintegration depending on

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starch. Pharmatose DCL 40 -lactose and anhydrous lactitol DFE Pharma Spherical shape particle with 92 good flowability, good β binding property and not hygroscopic Starch 1500 Amylose, amylopectin, and starch Colorcon It is a directly compressible, 93 free-flowing, USP grade of partially hydrolyzed cornstarch. The tablets produced disintegrates very fast Pearlitol SD Granulated mannitol Roquette Suitable for chewable tablet 73 application with good mouthfeel and palatability Advantose FS-95 Fructose and starch SPI Polyols Good mouthfeel and fast 90 disintegration property. Suitable for nutraceuticals and chewable vitamin applications Finlac DC Directly compressible lactitol Cultor Food Science Direct compression grade. 94 Good mouthfeel and fast disintegration property. Suitable for nutraceuticals and chewable vitamin applications Plasdone S-630 Vinyl acetate and vinyl pyrolidone ISP Good roller compaction 24 binder, improved hardness and better drug dissolution profile Lycatab C Pregelatinized starch Roquette Suitable for moisture 95 sensitive API. Copovidone Kollidon VA 64 and plasdone S630 Ashland Excellent flow properties 24 and dry binder Ludiflash Mannitol, crospovidone and polyvinyl BASF Suitable for high-speed 41 acetate tableting, low friability, and good flowability Orocell 200 and Orocell Spheronized mannitol Pharmatrans Sanaq Filler-binder with high 41 400 dilution potential and good disintegrating property Cel-O-Cal Microcrystalline cellulose and FMC Biopolymer Directly compressible binder 41 calcium sulphate Tablettose Spray dried lactose (agglomerated Meggle Good flowability and direct 96 form) compressible Xylitab and sodium Danisco Directly compressible and 97 carboxymethylcellulose good palatability StarCap 1500 Maize starch and pregel starch Colorcon Tablet disintegration and 98 dissolution independent of pH Vitacel VE-650 Microcrystalline cellulose and FMC Biopolymer Suitable for direct 97 calcium carbonate compression and encapsulation LustreClear Microcrystalline cellulose and FMC Biopolymer Efficient Tablet coating with 2 short hydration time prior to coating and the first drying time Pharmaburst system, made from SPI Pharma High compatibility, high 99 compendia ingredients loading in, small tablets, smooth mouth, feel, rapid, disintegration Effersoda Sodium bicarbonate and sodium SPI Pharma Improve the stability of the 2 carbonate Effervescent product Sorbcel M Mannitol, polyethylene glycol, Blanver Effervescent excipients, 2 polyvinylpyrrolidone, citric acid and Homogeneous and stable sodium bicarbonate mix of excipients that dissolves completely and rapidly, resulting in a clear solution free of insoluble residues Sorbcel E Sorbitol, mannitol, Blanver Effervescent excipients, 2 polyvinylpyrrolidone, citric acid and A homogeneous and stable sodium bicarbonate mix of excipients that dissolves completely and rapidly, resulting in a clear solution free of

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insoluble residues Fujicalin DCP anhydrous Fuji Chemicals Directly compressible, 100 exceptional high flow and rapid disintegration Neusilin Amorphous magnesium Fuji Chemicals Improve flow, anti-caking, 101 aluminometasilicate improve Compressibility and to make solid dispersion F-Melt Carbohydrate, disintegrant and DCP Fuji Chemicals Directly Compressible, oral 51 Disintegrating time less than 30 seconds, highly flowable with minimum or no sticking/capping Sepitrap 80 Polysorbate 80 Seppic Improves the bioavailability 95 of APIs with low solubility. It can be used in direct compression processes Sepitrap 4000 Ethoxylated Seppic Improves the bioavailability 95 hydrogenated castor of APIs with low solubility. It oil can be used in direct compression processes Tap-400 Processed tartaric acid pellet Pharmatrans As an acidic core for drug 2 Delivery technologies

Future trend REFERENCES Traditional inert excipients with lack of desired functionalities have 1. Godbole AM, Somnache SN, Thakker SP, Iliger SR, Patel BV, drawn the attention of pharmaceutical formulator in developing new Suryawanshi SD. Coprocessed directly compressible excipients: co-processed adjuvants. The recent developments in the field of a review. Uni J Pharm 2013;2:57-70. excipients, advancement in high-speed manufacturing machinery 2. Atul P, Subrata K, Ganga S. A review on co-processed excipients: and novel co-processing techniques have further added driving force a novel approach in formulation development. IJRAPI for the growth of this field. An exploration of solid-state properties 2013;3:25-41. of excipients and its impact on functionality is further going to fuel 3. The International Pharmaceutical Excipient Council Excipient this trend. Moreover, increase cost in developing new chemical Composition Guide. Europe; 2009. entity and an increasing preference for the direct compaction 4. Chaudhari PD, Phatak AA, Desai U. A review: co-processed process create a significant opportunity for the development of high- excipients–an alternative to novel chemical entities. Int J Pharm functionality co-processed excipients. It is predicted that the Chem Sci 2012;1:1480-98. development of tailor-made designed excipients complying with 5. Chukwu A. Key points in pharmaceutical formulation and safety, performance, and regulatory issues is a current and future industrial pharmacy. Nsukka: Mike Social Press; 2001. p. 1-5. trend in excipient technology [95]. With advantages offered by the 6. Nachegari SK, Bansal AK. Coprocessed excipients for solid upcoming newer combination of excipients and newer methods of dosage forms. Pharm Tech 2004;28:52-64. co-processing, co-processed excipients are for sure going to gain 7. Okore VC, Adikwu MU. Application of in attraction both from academia and pharmaceutical industry [102]. pharmaceutical sciences. In: Polymers and polymer Furthermore, it opens the opportunity for development and use of applications. Nsukka: Jolyn Publishers; 2009. p. 49-63. single multifunctional excipients rather than multiple excipients in 8. Reimerdes D, Aufmuth KP. Tableting withcoprocessed lactose- formulation [103]. cellulose excipient. Manufac Chem 1992;63:23-4. 9. Patel SS, Patel NM. Recent trends in direct compression CONCLUSION technology. Pharma Buzz 2007;2:24-34. The co-processed excipients play a pivotal role in formulating 10. Pakhale BA, Shinkar DM, Saudagar RB. Co-processed excipient: stable, result oriented drug delivery system with an improved an overview. World J Pharm Res 2014;4:454-69. physical, chemical and mechanical properties [104]. Furthermore, 11. Tobyn MJ, McCarthy GP, Staniforth JN, Edge S. co-processed excipients solve the issues of precompression Physicochemicalcomparison between microcrystalline parameters, compressibility, palatability, disintegration, cellulose and silicified microcrystalline cellulose. Int J Pharm dissolution, and sticking which conventional individual excipients 1998;169:183–94. might have. Co-processed excipient is a promising tool in 12. Ugoeze KC, Nkoro VO. The physico-technical properties of a pharmaceutical excipient development [105]. The existing co- multicomponent Lentinus tuberregium based co-processed processed adjuvants cannot fulfill all the functionalities required excipient (Fizlent). Am J Pharma Pharmacol 2015;2:13-20. for preparation of various novel formulations. Cost is another 13. Michael J, Tobyn GP, McCarthy I, John N, Staniforth SE. factor that incurs increased the price of the final product. So, there Physicochemical comparison between microcrystalline is enough scope of development of new co-processed excipients to cellulose and silicified microcrystalline cellulose. Int J Pharm meet the demand of pharmaceutical industries. It is expected that 1998;169:183-94. advanced research in academia and pharmaceutical industry will 14. Sudhir B, Vinay J, Shailesh S. Orally disintegrating tablets: a surely bridge this gap in the near future. review. Drug Invent Today 2010;2:81-8. 15. Moreton RC. Tablet excipients to the year 2001: a look into ACKNOWLEDGMENT thecrystal ball. Drug Dev Ind Pharm 1996;22:11-23. 16. Rasenack N, Muller BW. Crystal habit and tableting behavior. The authors would like to acknowledge Pioneered Scientist Int J Pharm 2002;244:45-57. Innovation Fund (PSIF grant, grant no: Proj-In-FPS-007) for 17. Liew KB, Peh KK, Tan YTF. Orally disintegrating dosage forms: sponsoring the research project. We thank Faculty of Pharmaceutical breakthrough solution for non-compliance. Int J Pharm Pharm Science, UCSI University for providing facilities. Sci 2013;5:4-8. CONFLICT OF INTERESTS 18. Shangraw RF, Leiberman HA, Lachman L, Schwatz JB. Pharmaceutical dosage forms: tablets. New York: Marcel The authors report no declaration of interest Dekker; 1990. p. 195-246.

7 Liew et al. Int J Pharm Pharm Sci, Vol 11, Issue 1, 1-9

19. Shangraw RF, Demarest DA. A survey of current industrial 44. Bauer K, Kleeli K. Product based on co- practicesin the formulation and manufacture of tablets and processed with an insolubledisintegrant, process for its capsules. Pharm Tech 1993;17:32-44. preparation and the use. EP1167433; 2002. 20. Norman AA. Tablet manufactured by direct compression. 45. Bauer KH. Coprocessed product with Encyclopedia of pharmaceutical technology. New York: Informa insolublecarboxymethylcellulose. EP1070740, 2001. Healthcare USA; 2007;6:3673. 46. Bauer K, Streb M. Coprocessed granules of disintegrating 21. Banker UV. Role of ingredients and excipients in developing agents. EP1201709; 2002. pharmaceuticals. Manufact Chem 1994;65:32-4. 47. Hapgood KP, Tan MXL, Chow DWY. A method to predict nuclei 22. Rubinstein MH. Tablets pharmaceutics: the science of dosage of size distributions for use in models of wet granulation. Adv form. 1st edition. UK: Churchill; 1998. p. 304-21. Powder Technol 2009;20:293–7. 23. York P. Crystal engineering and particle design for the 48. York FP, Rowe RC. Process control and scale-up of powder compaction process. Drug Dev Ind Pharm pharmaceutical wetgranulation processes: a review. Eur J 1992;18:677-721. Pharm Biopharm 2000;52:269–77. 24. Marwaha M, Sandhu D, Marwaha RK. Coprocessing of 49. Liu JP, Zhang F, McGinity JW. Properties of lipophilic matrix excipients: a review on excipient development for improved tablets containing phenylpropanolamine hydrochloride prepared tabletting performance. Int J Appl Pharm 2010;2:41-2. by hot melt extrusion. Eur J Pharm Biopharm 2001;52:181-90. 25. Flores LE, Arellano RL, Esquivel JJD. Study of load capacity of 50. Bone A, Izebound E. Excipients on the move. IPEC Europe news. Avicel PH200 and cellactose, two direct compression excipients, Available from: http://www.ipec-europe.org/UPLOADS/ using an experimental design. Drug Dev Ind Pharm 2004_October.pdf. [Last accessed on 15 Aug 2015] 2000;26:465–9. 51. Patel RP, Patel MP, Suthar AM. Spray drying technology: an 26. Jivraj M, Martini LG, Thomson CM. An overview of the different overview. Indian J Sci Technol 2009;2:44-5. excipients useful for the direct compression of tablets. Pharm 52. Meggelaars MM, Biggelaar HA, Kussendrager, KD. Sci Technol Today 2000;3:58-63. Tabletingexcipient. US5534555, 1996. 27. Sherwood BE, Becker JW. A new class of high functionality 53. Staniforth J. Pharmaceutical superdisintegrant. excipients: silicified microcrystalline cellulose. Pharm Tech US20050100600; 2005. 1988;22:78–88. 54. Staniforth J. Pharmaceutical superdisintegrant. US6660303; 28. Smewing J. Powder flow analysis-the solution. Manufact Chem 2003. 2002;73:32-3. 55. Rao VU, Balasubramaniam J, Haldar RK. Coprocessedexcipient 29. Ambore SM, Tekale J, Gattani SG. Investigation of novel compositions. US20120178822; 2012. multifunctional co-processed excipient for direct compression. 56. Gohel MC, Jogani PD. An investigation in direct compression World Appl Sci J 2014;31:801-10. characteristics of co-processed lactose-starch using an 30. Belda PM, Mielck JB. The tableting behavior of Cellactose experimental design. Indian J Pharm Sci. 2003;65:31-8. compared with mixtures of with lactoses. Eur J 57. Cucula EJ, Luengo MG, Ortega AS. Modified calcium Pharm Biopharma 1996;42:325–30. phosphateexcipient. US7364755; 2008. 31. Patel RP, Bhavsar M. Direcetly compressible materials via co- 58. Mehra DK, West KP, Wiggins DJ. Coprocessed microcrystalline processing. Iran J Pharm Res 2009;1:745-53. cellulose and calcium carbonate composition and its 32. Reimerdes D. The near future of tablet excipients. Manufact preparation. EP0193984; 1986. Chem 1993;64:14–5. 59. Lang S. Direct tableting auxillary US5006345; 1991. 33. Armstrong NA, Palfrey LP. The effect of machine speed on the 60. Menon A, Gillece T, Chakrabarti S. Co-processing method for consolidation of four directly compressible tablet diluents. J making a free-flowing compressible powder and tablet, US Pharm Pharmacol 1989;41:149. 5560927 A; 1996. 34. Marwaha M, Sandhu D, Marwaha RK. Coprocessing of 61. Sherwood BE, Hunter EA, Staniforth JH. Pharmaceutical excipients: a review on excipient development for improved excipient having improved compressibility. US5585115; 1996. tableting performance. Int J Appl Pharm 2010;2:41-7. 62. Ratnaraj S, Reilly Jr. WJ. Chewable pharmaceutical tablets. 35. Panda B, Raot A, Kilor V. Co-processed excipients: an overview US5686107; 1997. of formulation aspects, physical characteristics, and role as a 63. Bowe KE. Recent advances in sugar-based excipients. Pharma pharmaceutical aid. Pharmatutor Art 1049; 2010. Sci Technol Today 1998;1:166–73. 64. Augello M, Vladyka RS, Dell SM. Taste masked pharmaceutical 36. Limwong V, Sutanthavibul N, Kulvanich P. Spherical composite particles of rice starch and microcrystalline cellulose: a new co- composition. US5904937; 1999. 65. Augello M, Reier GE. Microcrystalline cellulose/alginate wet processed excipient for direct compression. AAPS granulation excipient/binder, US5985323; 1999. PharmSciTech 2004;5:40-9. 66. Ibrahim N, Saraiya M. Co-processed botanical plant 37. Gohel MC, Parikh RK, Brahmbhatt BK, Shah AR. Preparation composition. US6232351; 2001. and assessment of novel co-processed superdisintegrant 67. Buliga GS, Tuason DC, Venables AC. Texture and stabilizer consisting of crospovidone and sodium starch glycolate: a compositions. US6440474; 2002. technical note. AAPS PharmSciTech 2007;8:63-9. 68. Cucula EJ, Luengo MG, Lana IM. Extended-release venlafaxine 38. Jacob S, Shirwaikar AA, Joseph A, Srinivasan KK. Novel besylate tablets. US20060018963; 2006. coprocessed excipients of mannitol and microcrystalline 69. Norman GT, Nuguru KS, Amin AF, Chandar S. Co-processed cellulose for preparing fast dissolving tablets of glipizide. carbohydrate system as a quick-dissolve matrix for solid Indian J Pharm Sci 2007;69:633-9. dosage forms. US7118765; 2006. 39. Barakat NS, Elbagory IM, Almurshedi AS. Controlled release 70. Haldar R, Ray DB, Bee TG, Etienne S, Cheng S. Synergistic carbamazepine matrix granules and tablets comprising binder compositions, a method for making same, and tablets of lipophilic and hydrophilic components. Drug Delivery an active and said binder having advantageous hardness and 2009;16:57-65. friability. US20070122472; 2007. 40. Kumari MS, Prasanthi CH, Sudha Bhargavi CH, Kumari MP, 71. Li J, Carlin B, Ruszkay T. Co-processed microcrystalline and Ushasri S. Reassessment of novel co-processed multifunctional as an excipient for tablet formulations. excipients. IRJPAS 2013;3:122-8. US20080131505; 2008. 41. Gohel MC, Jogani PD. A review of co-processed directly 72. Gandhi AS, Bagde P, Morvekar HN, Pilgaonkar PS, Rustomjee compressible excipients. J Pharm Pharm Sci 2005;8:76-93. MT. Orally disintegrating tablets. US20090208576; 2009. 42. Adeyeye MC. Roller compaction and milling pharmaceutical 73. Nagendrakumar D, Raju SA, Shirsand SB, Para MS. Design of unit processes: Part I. Am Pharm Rev 2000;3:37–42. fast dissolving granisetron HCL tablets using novel co- 43. Teng Y, Qiu ZH, Wen H. Systematical approach of formulation processed superdisintegrants. J Biosci Technol 2009;1:8-14. and process development using roller compaction. Eur J Pharm 74. Ayyappan J, Umapathi P, Quine D. Development and evaluation Biopharm 2009;73:219–29. of a directly compressible co-processed multifunction

8 Liew et al. Int J Pharm Pharm Sci, Vol 11, Issue 1, 1-9

sustained release agent for tablets. Int J Pharm Pharm Sci 90. Uma Rani G, Begum N. Overview of co-processed excipients 2010;2:201-5. used to improve tabletting performance. J Adv Drug Delivery 75. Dey NS, Panda BP, Rao MEB. Effect of co-processed direct 2014;1:1-6. compressible vehicles on fast dissolving tablets. Int J Phytother 91. Michoel A, Rombaut P. Comparative evaluation of co-processed Res 2010;2:771-83. lactose and microcrystalline cellulose with their physical 76. Davar N, Kavalakatt P, Pather I, Ghosh S. Polyethylene glycol- mixtures in the formulation of folic acid tablets. Pharm Dev coated sodium carbonate as a pharmaceutical excipient and Technol 2002;7:79-87. compositions produced from the same. US20100266682; 2010. 92. Bolhuis GK, Chowhan ZT. Materials for direct compression, 77. Adnan B, Iyad R, Mayyas ALR, Stephen AL, Babur ZC. A novel pharmaceutical powder compaction technology, USA: Marcel multifunctional pharmaceutical excipient: Modification of the Dekker; 1996;7:419-99. permeability of starch by processing with magnesium silicate. 93. Monedero Perales MC, Munoz Ruiz A, Velasco Antequera MV, Int J Pharm 2011;411:18-26. Jimenez-Castellanos MR. Study of the compaction mechanisms 78. Akram M, Naqvi SBS, Gauhar S. Development of co-processed of lactose-based direct compression excipients using micro granules for direct compression. IJPPS 2011;3:64-9. indentation hardness and heckel plot. J Pharm Pharmacol 79. Al Omari MM, Badwan AA, Daragmeh NH. Pharmaceutical 1994;46:177-81. excipient, a method for its preparation and use thereof. 94. Soujanya B, Pavani PG, Murthy TEGK. Co-processing of EP2384742; 2011. excipients: A review on excipient development for improved 80. Deorkar N, Farina J, Miinea L, Randive S. Directly compressible tabletting performance. RJPDFT 2015;7:149-55. high functionality granular dibasic calcium phosphate-based 95. Desai U, Chavan R, Mhatre P, Chinchole R. A review: co- co-processed excipient. US20110229527; 2011. processed excipients. Int J Pharm Sci Rev Res 2012;12:93-105. 81. Olowosulu AK, Avosuahi O, Isah AB, Ibrahim MA. Formulation 96. Bolhuis GK, Zuurman K. Tableting properties of experimental and evaluation of novel co-processed excipients of maize starch and commercially available lactose granulations for direct and acacia gum (StarAc) for direct compression tabletting. compression. Drug Dev Ind Pharm 1995;21:2057-71. IJPRI 2011;2:39-45. 97. Hauschild K, Picker KM. Evaluation of a new co-processed 82. Thoorens G, Leclercq B, Ruszkay T. Microcrystalline compound based on lactose and maize starch for tablet celluloseand calcium phosphate compositions useful as formulation. AAPS Pharm Sci 2004;6:1-12. pharmaceutical excipients. WO2011056775; 2011. 98. Muzikova J, Eimerova I. A study of the compaction process and 83. Gangurde AB, Amin PD. Formulation development and the properties of tablets made of a new co-processed starch evaluation of metformin hydrochloride sustained release excipient. Drug Dev Ind Pharm 2011;37:576-82. matrix tablet by using directly compressible co-processed 99. Brniak W, Jachowicz R, Krupa A, Skorka T, Niwinski K. excipient. World J Pharm Pharm Sci 2013;2:5296-308. Evaluation of co-processed excipients used for direct 84. Pawar AY, Patil SH, Jadhav KR, Baviskar SR. Formulation and compression of orally disintegrating tablets (ODT) using evaluation of matrix tablet of venlafaxine HCl by using directly novel disintegration apparatus. Pharm Dev Technol compressible co-processed excipient. Int J Pharm Pharm Sci 2013;18:464-74. 2014;6:504-11. 100. Schlack H, Bauer Brandl A, Schubert R, Becker D. Properties of 85. Schmidt PC, Rubensdorfer CJ. Evaluation of ludipress as a fujicalin®, a new modified anhydrous dibasic calcium multipurpose excipient for direct compression. Part 1. Powder phosphate for direct compression: comparison with dicalcium characteristics and tableting properties. Drug Dev Ind Pharm phosphate dihydrate. Drug Dev Ind Pharm 2001;27:789-801. 1994;20:2899-925. 101. Kanojia N, Kaur L, Nagpal M, Bala R. Modified excipients in 86. Casalderrey M, Souto C, Concheiro A, Gomea Amoza JL, novel drug delivery: the need of the day. IJTRM 2013;1:81–107. Martinez Pacheco R. A comparison of cellactose with TwoAd 102. Garg N, Dureja H, Kaushik D. Co-processed excipients: a patent hoc processed lactose-cellulose blends as direct compression review. Recent Pat Drug Delivery Formula 2013;7:73-83. excipients. Chem Pharm Bull 2000;48:458-63. 103. Kumare MM, Marathe RP, Kawade RM, Ghante MH, Shendarkar 87. Rizzuto AB, Chen AC, Veiga ME. Modification of the sucrose GR. Design of fast dissolving tablet of atenolol using novel co- crystals structure to enhance pharmaceutical properties of processed. Asian J Pharm Clin Res 2013;6:81-5. excipient and drug substance. Pharm Tech 1984;8:32-9. 104. Parfati N, Rani KC, Meilany M. The effect of coprocessed 88. Bolhuis GK, Veen B, Wu YS, Zuuraman K, Frijlink HW. superdisintegrants ratio (crospovidone-sodium starch glycolate) Compaction mechanism and tablet strength of unlubricated to the physicochemical characteristics of atenolol orally and lubricated silicified microcrystalline cellulose. Eur J Pharm disintegrating tablets. Asian J Pharm Clin Res 2018;11:318-24. Biopharm 2005;59:133-8. 105. Parfati N, Rani KC, Charles N, Geovany V. Preparation and 89. Rojas J, Kumar V. Comparative evaluation of silicified evaluation of atenolol- -cyclodextrin orally disintegrating microcrystalline cellulose as a direct compression vehicle. Int J tablets using co-process crospovidone-sodium starch glycolate. Pharm 2011;416;120-8. Int J Appl Pharm 2018;10:β190-4.

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